Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation

Pedroza-González, Alexander; Xu, Kangling; Wu, Te-Chia; Aspord, Caroline; Tindle, Sasha; Marches, Florentina; Gallegos, Michael; Burton, Elizabeth C.; Savino, Daniel A.; Hori, Tomohide; Tanaka, Yuetsu; Zurawski, Sandra; Bover, Laura; Liu, Yong Jun; Banchereau, Jacques; Palucka, A. Karolina

doi:10.1084/jem.20102131

Cited by 220 publications

(228 citation statements)

References 62 publications

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“…Importantly, residual tumors from CTX-treated patients also contained reduced percentages of B cells and CD4 + T cells. Tumor-infiltrating CD4 + T cells in BC are known to express the T H 2 cytokines IL-4 and IL-13 concomitantly with the production of IFN-γ (25,26), consistent with coexpression of CXCR3 and CCR4 (38, 39) as we observed herein. It remains to be determined whether cytokine production by CD4 + T cells is altered by neoadjuvant CTX; however, the combined reduction in both CD4 + T cells and B cells is indicative of a favorable shift away from a T H 2 microenvironment.…”

Section: Discussionsupporting

confidence: 88%

“…CD4 + T cells isolated from human BC produce high levels of type II helper (T H 2) cytokines including IL-4 and IL-13 (25,26), which are significant in light of studies demonstrating that several protumor activities of TAMs are regulated by IL-4 derived from CD4 + T cells (1,27). Based on these findings, we recently reported that infiltration by CD68 + , CD4 + , and CD8 + immune cells in human BC is predictive of overall survival, and that the ratio of CD68 to CD8a mRNA in tumor tissue correlates with complete pathologic response (pCR) in patients undergoing neoadjuvant chemotherapy (CTX) for early stage BC (6).…”

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confidence: 99%

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Leukocyte composition of human breast cancer

Ruffell¹,

Rugo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

405

300

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Retrospective clinical studies have used immune-based biomarkers, alone or in combination, to predict survival outcomes for women with breast cancer (BC); however, the limitations inherent to immunohistochemical analyses prevent comprehensive descriptions of leukocytic infiltrates, as well as evaluation of the functional state of leukocytes in BC stroma. To more fully evaluate this complexity, and to gain insight into immune responses after chemotherapy (CTX), we prospectively evaluated tumor and nonadjacent normal breast tissue from women with BC, who either had or had not received neoadjuvant CTX before surgery. Tissues were evaluated by polychromatic flow cytometry in combination with confocal immunofluorescence and immunohistochemical analysis of tissue sections. These studies revealed that activated T lymphocytes predominate in tumor tissue, whereas myeloid lineage cells are more prominant in “normal” breast tissue. Notably, residual tumors from an unselected group of BC patients treated with neoadjuvant CTX contained increased percentages of infiltrating myeloid cells, accompanied by an increased CD8/CD4 T-cell ratio and higher numbers of granzyme B-expressing cells, compared with tumors removed from patients treated primarily by surgery alone. These data provide an initial evaluation of differences in the immune microenvironment of BC compared with nonadjacent normal tissue and reveal the degree to which CTX may alter the complexity and presence of selective subsets of immune cells in tumors previously treated in the neoadjuvant setting.

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Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

Leukocyte composition of human breast cancer

Ruffell¹,

Rugo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

405

300

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“…The IL-4-induced decreased antimicrobial peptide secretion by keratinocytes would be one of the potential mechanisms responsible for this increased susceptibility (49). Finally, it has also been recently described that, in a breast cancer, thymic stromal lymphopoietin produced by epithelial cancer cells can induce the development of Th2 cells that promote tumor growth (50). Thus, our results suggest that Th2-derived IL-4 could also impact on the function of pre-existing memory CD8 T cells and contribute to the pleiotropic regulation of the immune response associated with Th2-inducing pathologies.…”

Section: Discussionmentioning

confidence: 98%

Negative Regulation of NKG2D Expression by IL-4 in Memory CD8 T Cells

Ventre

Brinza

Schicklin

et al. 2012

The Journal of Immunology

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IL-4 is one of the main cytokines produced during Th2-inducing pathologies. This cytokine has been shown to affect a number of immune processes such as Th differentiation and innate immune responses. However, the impact of IL-4 on CD8 T cell responses remains unclear. In this study, we analyzed the effects of IL-4 on global gene expression profiles of Ag-induced memory CD8 T cells in the mouse. Gene ontology analysis of this signature revealed that IL-4 regulated most importantly genes associated with immune responses. Moreover, this IL-4 signature overlapped with the set of genes preferentially expressed by memory CD8 T cells over naive CD8 T cells. In particular, IL-4 downregulated in vitro and in vivo in a STAT6-dependent manner the memory-specific expression of NKG2D, thereby increasing the activation threshold of memory CD8 T cells. Furthermore, IL-4 impaired activation of memory cells as well as their differentiation into effector cells. This phenomenon could have an important clinical relevance as patients affected by Th2 pathologies such as parasitic infections or atopic dermatitis often suffer from viral-induced complications possibly linked to inefficient CD8 T cell responses.

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“…However, immune regulation in the liver and tumor environment may contribute to tumor outgrowth and limit the efficacy of immunotherapeutic strategies. 10,11 In support of this we and others have described the presence of regulatory CD4 C Foxp3 C T cells in liver tumors, that suppress local antitumor immunity and that are associated with poor patient prognosis. [12][13][14][15][16] Liver TiTreg are characterized by high expression of glucocorticoidinduced tumor necrosis factor receptor related gene (GITR), CTLA-4 and inducible T cell co-stimulator (ICOS).…”

Section: Introductionmentioning

confidence: 57%

GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cellsex vivo

et al. 2015

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Sprengers (2015) GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cells ex vivo, OncoImmunology, 4:12, e1051297, DOI: 10.1080/2162402X.2015 Keywords: cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), hepatocellular carcinoma (HCC), liver metastases from colorectal cancer (LM-CRC), regulatory T cells (Treg)In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITRligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti-Treg. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor-infiltrating CD4 C Foxp3C Treg, thereby restoring proliferation and cytokine production by effector T cells. Importantly, combined treatment with low doses of both molecules exhibited stronger recovery of T cell function compared with either treatment alone. Our data suggest that in patients with primary and secondary liver cancer both GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression.

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Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation

Abstract: TSLP released from human breast cancer cells promotes OX40L expression on DCs, and these OX40L-expressing DCs drive development of inflammatory Th2 cells which promote breast tumor development.

Cited by 220 publications

References 62 publications

Leukocyte composition of human breast cancer

Leukocyte composition of human breast cancer

Negative Regulation of NKG2D Expression by IL-4 in Memory CD8 T Cells

GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cellsex vivo

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